Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1

Chittaranjan Das, Quyen Hoang, Cheryl A. Kreinbring, Sarah J. Luchansky, Robin K. Meray, Soumya S. Ray, Peter T. Lansbury, Dagmar Ringe, Gregory A. Petsko

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

The ubiquitin C-terminal hydrolase UCH-L1 (PGP9.5) comprises >1% of total brain protein but is almost absent from other tissues [Wilkinson, K. D., et al. (1989) Science 246, 670-673]. Mutations in the UCH-L1 gene have been reported to be linked to susceptibility to and protection from Parkinson's disease [Leroy, E., et al. (1998) Nature 395, 451-452; Maraganore, D. M., et al. (1999) Neurology 53, 1858-1860]. Abnormal overexpression of UCH-L1 has been shown to correlate with several forms of cancer [Hibi, K., et al. (1998) Cancer Res. 58, 5690-5694]. Because the amino acid sequence of UCH-L1 is similar to that of other ubiquitin C-terminal hydrolases, including the ubiquitously expressed UCH-L3, which appear to be unconnected to neurodegenerative disease, the structure of UCH-L1 and the effects of disease associated mutations on the structure and function are of considerable importance. We have determined the three-dimensional structure of human UCH-L1 at 2.4-Å resolution by x-ray crystallography. The overall fold resembles that of other ubiquitin hydrolases, including UCH-L3, but there are a number of significant differences. In particular, the geometry of the catalytic residues in the active site of UCH-L1 is distorted in such a way that the hydrolytic activity would appear to be impossible without substrate induced conformational rearrangements.

Original languageEnglish (US)
Pages (from-to)4675-4680
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number12
DOIs
StatePublished - Mar 21 2006
Externally publishedYes

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Ubiquitin Thiolesterase
Hydrolases
Ubiquitin
Parkinson Disease
Crystallography
Mutation
Neurology
Neurodegenerative Diseases
Amino Acid Sequence
Catalytic Domain
Neoplasms
X-Rays
Brain
Genes
Proteins

Keywords

  • Neurodegeneration
  • Ubiquitin ligase
  • Ubiquitination
  • X-ray crystallography

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1. / Das, Chittaranjan; Hoang, Quyen; Kreinbring, Cheryl A.; Luchansky, Sarah J.; Meray, Robin K.; Ray, Soumya S.; Lansbury, Peter T.; Ringe, Dagmar; Petsko, Gregory A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 12, 21.03.2006, p. 4675-4680.

Research output: Contribution to journalArticle

Das, Chittaranjan ; Hoang, Quyen ; Kreinbring, Cheryl A. ; Luchansky, Sarah J. ; Meray, Robin K. ; Ray, Soumya S. ; Lansbury, Peter T. ; Ringe, Dagmar ; Petsko, Gregory A. / Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 12. pp. 4675-4680.
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AU - Kreinbring, Cheryl A.

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AU - Meray, Robin K.

AU - Ray, Soumya S.

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AU - Ringe, Dagmar

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